Local anesthetics are drugs that block nerve impulse generation and conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. A local anesthetic can cause both sensory and motor paralysis in the area where they are applied. Many kinds of compounds interfere with conduction, but they often permanently damage the nerve cell. The advantage of a good local anesthetic is that its action is reversible and is followed by essentially complete recovery of the nerve function with no evidence of structural damage.
A good local anesthetic should combine several properties; it should not be irritating to the tissue to which it is applied, nor should it cause any permanent damage to nerve structure. Also, its systemic toxicity should be low. Therefore, the therapeutic index is an important factor in evaluating novel local anesthetics. Since this can vary greatly, there is a constant search for new, more effective, and safer agents.
It is also important that the onset of anesthesia should be short, but that the anesthetic action last long enough for surgical procedure to take place, yet not so long as to entail an extended period of recovery. Occasionally, a local anesthetic action lasting for days or even weeks is desirable, such as in the control of chronic pain. Unfortunately,the available agents for long-term pain control have high local toxicity, resulting in neurolysis with necrosis of the surrounding tissues. Such toxicity may result in complete paralysis if it occurs in the vicinity of the spinal cord.
Most of the useful local anesthetics contain hydrophobic and hydrophilic domains that are generally separated by an intermediate alkyl chain. The hydrophilic group is usually a tertiary amine, the hydrophobic portion is usually aromatic. In almost all cases, linkage to the aromatic ring is of the ester or amide type. Changes in any part of the molecule alter the anesthetic potency of the compound as well as its toxicity. For example, increasing the length of the intermediate alkyl chain results in more potent anesthetic properties, but also in increased toxicity. These relationships have been reviewed by Buchi and Perlia (Buchi, J. X., Perlia [1971] In: Local Anesthetics, Vol. 1, International Encyclopedia of Pharmacology and Therapeutics, Sect. 8, Lechat, P., ed, Pergamon Press Ltd., Oxford, pp 39-130).
Tetracaine is a known local anesthetic (FIG. 1). Tetracaine derivatives of the N-alkyl type have been described in the scientific literature (Wang, G. K., M. Vladimirov, H. Shi, W. M. Mok, J. G. Thalhammer, D. C. Anthony [1998] Anesthesiology 88:417-428). These derivatives have very long-lasting anesthetic properties and the highest homologs of the series are neurolytic, normally an unwanted form of local toxicity, which the authors claim as a desirable property for use in destruction of pathogenic regions that produce pain (Wang, G. K., M. Vladimirov, C. Quan, W. M. Mok, J. G. Thalbammer, D. C. Anthony [1996] Anesthesiology 85(6):1386-1394), as for example in sciatic nerve.